T-lymphocyte deficient mice and immunocompromised humans have significantly higher incidence of various cancers, indicating that T lymphocytes play a critical role in tumor surveillance and rejection. Understanding how T cells develop and respond to T cell receptor (TCR) signals in a murine experimental model system will enhance our understanding of how T cells in immuno-competent humans perform surveillance against tumors. The TCR is a transmembrane receptor which has multiple signaling subunits. There is a gap in knowledge about the unique functions of individual signaling subunits of the TCR. The primary objective of his proposal is to understand how T lymphocytes respond to external stimuli when a key component of their TCR is absent. We have focused on the role of the CD3delta subunit in TCR signal transduction. CDSdelta deficiency has been observed in humans and results in an immunodeficiency syndrome. Unlike the other TCR subunits, CDSdelta is unique, in that not all TCR signaling events require this subunit. Our preliminary studies indicate that CD3delta deficient TCR signals are insufficient for the generation mature T cells in vivo, even though these receptors can signal if stimulated in vitro. This finding led to our central hypothesis that CDSdelta is responsible for the TCR to interact with CD4 or CDS co-receptors so that it can recognize MHC:peptide ligands on antigen presenting cells. We propose to use CDSdelta deficient cell lines grown in our tissue culture laboratory and murine models supplemented by CDSdelta transgenes to identify the molecular mechanism of this protein's contribution to TCR signal transduction. We will perform molecular biological and biochemical experiments that will lead to the cause of the defect observed during immune system development in the absence of CDSdelta. The objective of this proposal is to 1) attempt to overcome this developmental defect, 2) determine the mechanism of CDSdelta deficient TCR signals, 3) determine if CDSdelta interacts with co-receptor molecules on the surface of T lymphocytes. The genetically modified cell lines and mice created in this proposal will enable us to explore the function of ligand dependent and ligand independent signaling in T lymphocytes. A better understanding of CDSdelta deficient TCR signals will allow us to overcome the immunodeficiencies (and associated higher cancer risk) in patients that lack this protein.